The following description is provided to assist the understanding of the reader. None of the information provided or references cited is admitted to be prior art to the present invention.
Hypophosphatemic rickets presents with rickets and osteomalacia in growing children and associated bone abnormalities, such as bowing of the lower extremities, and osteomalacia in adults. Most cases of X-linked hypophosphatemic rickets, which shows a prevalence of about 1:20,000 live births, are associated with X-linked dominant loss-of-function mutations in the gene PHEX or in the case of autosomal dominant hypophosphatemic rickets, an autosomal dominant gain-of-function mutations in the gene FGF23. X-linked hypophosphatemia (XLH) is characterized by a renal tubular abnormality resulting in phosphate wasting and consequent hypophosphatemia. XLH is the prototypic renal phosphate wasting disorder, characterized in general by progressively severe skeletal abnormalities and growth retardation. The hyp-mouse model harbors a homologous mutation and is an excellent mimic of the human disease. Indeed, much of our understanding of the pathophysiology of XLH derives from studies of the murine homologue.
In contrast, tumor-induced osteomalacia (TIO) is a sporadic condition characterized by remission of the bone disease after resection of a coexisting tumor. The tumors have been of mesenchymal origin in the large majority of patients. However, the observation of TIO concurrent with breast carcinoma, prostate carcinoma, oat cell carcinoma, small cell carcinoma, multiple myeloma, and chronic lymphoctytic leukemia indicates that the disease is likely secondary to a variety of tumors, including those of epidermal and endodermal derivation. Both XLH and TIO have an elevated serum FGF23 level and associated abnormal proximal renal tubular function, resulting in hypophosphatemia, as well as rickets and osteomalacia and the bone abnormalities associated with these mineralization defects. In addition, the disorders are characterized by low or inappropriately normal serum 1,25-dihydroxyvitamin D [1,25(OH)2D] levels.
The gene that is associated with XLH is PHEX (phosphate-regulating gene with homologies to endopeptidases on the X-chromosome), which encodes a 749 amino acid type I membrane protein. Various mutations in the PHEX gene, which are believed to impair the function of the PHEX protein, have been identified in XLH patients; however, the molecular mechanism by which a functional loss of this gene product leads to hypophosphatemic rickets is still uncertain.
The clinical expression of XLH is widely variable, ranging from a mild abnormality, the apparent isolated occurrence of hypophosphatemia, to severe rickets and/or osteomalacia. In children, the most common clinically evident manifestations include short stature and limb deformities associated with rickets. The majority of children with the disease exhibit enlargement of the wrists and/or knees secondary to rickets, as well as bowing of the lower extremities and short stature. Additional signs of the disease may include late dentition, tooth abscesses secondary to poor mineralization of the interglobular dentine, and premature cranial synostosis. Many of these features do not become apparent until the age of 6 to 12 months or older. In spite of marked variability in the clinical presentation, bone biopsies in affected children and adults invariably reveal low turnover osteomalacia without osteopenia. The severity of the bone disorder has no apparent relationship to gender, the extent of the biochemical abnormalities, or the severity of the clinical disability. In untreated youths and adults, the serum 25(OH)D levels are normal and the concentration of 1,25(OH)2D is in the low to normal range. The paradoxical occurrence of hypophosphatemia and normal serum calcitriol levels is due to aberrant regulation of renal 25(OH)D-1α-hydroxylase activity. Studies in hyp- and gy-mice, the murine homologues of the human disease, have established that defective regulation is confined to the enzyme localized in the proximal convoluted tubule, the site of abnormal phosphate transport.
Patients with TIO usually present with bone and muscle pain, muscle weakness, and, occasionally, recurrent fractures of long bones. Additional symptoms common to younger patients are fatigue, gait disturbances, slow growth, and skeletal abnormalities, including bowing of the lower extremities. The duration of symptoms before diagnosis ranges from 2.5 months to 19 years. The age at diagnosis is generally the sixth decade, with a range of 7 to 74 years. Approximately 20% of the patients are younger than 20 years at presentation. The biochemical abnormalities of the disorder include hypophosphatemia and an abnormally low renal tubular maximum for the reabsorption of phosphorus per liter of glomerular filtrate (TmP/GFR), indicative of renal phosphate wasting. The serum phosphorus values range from 0.7 to 2.4 mg/dL. Additional abnormalities include gastrointestinal malabsorption of phosphorus, which, coupled with renal phosphorus wasting, results in a negative phosphorus balance. Serum 25(OH)D is normal and serum 1,25(OH)2D inappropriately normal relative to the hypophosphatemia. Aminoaciduria, most frequently glycinuria, and glucosuria are occasionally present. Radiographic abnormalities include generalized osteopenia, pseudofractures, and coarsened trabeculae, as well as widened epiphyseal plates in children and bone biopsy evidence of osteomalacia in children and adults.